GMF 依赖性神经炎症和神经变性-猫眼课题宝

GMF 依赖性神经炎症和神经变性

批准号：

8666674

负责人：

ASGAR ZAHEER

金额：

$32.7万

依托单位：

UNIVERSITY OF IOWA

依托单位国家：

美国

项目类别：

财政年份：

2011

资助国家：

美国

项目状态：

已结题

起止时间：

2011-09-15 至 2016-05-31

来源：

https://reporter.nih.gov/project-details/8666674

关键词：

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-Methyl-4-phenylpyridinium Adenoviruses Affect Age American Animal Model Astrocytes Autopsy Behavioral Brain Cultured Cells Development Diagnosis Disease Experimental Animal Model Exposure to Gender Glia Maturation Factor Goals Human Human Pathology In Vitro Inflammation Inflammation Mediators Investigation Knock-out Knockout Mice Laboratories Lentivirus Vector Lewy Bodies Maintenance Mediator of activation protein Messenger RNA Microglia Molecular Profiling Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Neurons Normal tissue morphology Parkinson Disease Pathogenesis Pathology Production Proteins Reactive Nitrogen Species Reactive Oxygen Species Research Resistance Role Side Signal Transduction Small Interfering RNA Stimulus Techniques Testing Therapeutic Intervention Time Transfection Treatment Efficacy Wild Type Mouse base brain cell brain tissue chemokine comparative cytokine disorder control dopaminergic neuron effective therapy fetal motor deficit mouse model nervous system disorder neurochemistry neuroinflammation neuron loss neurotoxic novel novel therapeutic intervention overexpression pollutant prevent research study small hairpin RNA

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DESCRIPTION (provided by applicant): Parkinson's disease is progressive disabling and fatal. It is estimated that 60,000 new cases are diagnosed each year, joining the 1 million Americans who currently have Parkinson's disease, and there is no cure for this disease. PD is characterized by the presence of degenerating dopaminergic neurons, Lewy bodies and activated glia in brain. Although, the cause of PD is not clear, exposure to environmental neurotoxic pollutant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to be associated with the pathology of human PD and in animal models of PD. Invariably, activated glia are not only present but are also persistent in PD brains which could facilitate maintenance and progression of PD by secreting deleterious cytokines and chemokines. The glia maturation factor (GMF), discovered and characterized in our laboratory, is a conserved protein in mammalian brain/central nervous system. We already demonstrated the prominent role of GMF in activation of astrocytes and microglia by various factors and stimuli leading to death of neuronal cells. We hypothesize that GMF is also involved in pathogenesis of PD. This novel hypothesis is based on the demonstrated functions of GMF and our recent immuno-histological examinations that revealed numerous activated astrocytes, microglia and the prominence of GMF in nigrostriatal region of postmortem PD brains, as well as, in brains of experimental animal model of PD in which the changes in GMF, astrocytes and microglia preceded the loss of dopamine neurons. We forward three specific aims to support our hypothesis. Specific Aim 1 will examine the association between GMF and the pathology of PD. We will also examine whether GMF-dependent glial activation is required in the production of proinflammatory mediators that are responsible for degeneration of dopaminergic neurons. Specific Aim 2 will chart the comparative pathogenesis and progression of MPTP-induced dopaminergic neuronal loss in GMF-containing wild type and in GMF-deficient (GMF-KO) mice. We will compare the histopathological features, neurochemical changes, and behavioral motor deficits in Wt mice with GMF-KO mice. Specific Aim 3 will evaluate the suppression of neuroinflammation/neurodegeneration and therapeutic efficacy of our novel therapeutic approach of targeting GMF with GMF-specific siRNA to silence the GMF-signaling in MPTP-intoxicated mice.

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